Throughout this application various publications are referred to in brackets. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
The widespread use of nuclear energy in diagnosis, radiotherapy and the generation of electrical power has resulted in the realization of the serious and dangerous effects of radiation exposure. As evidenced by the Chernobyl nuclear disaster of 1986 and more recently with the radiation leak at the Fukushima I Power plant, massive unforeseen radiation exposure is a possibility. In the wake of the Sep. 11, 2001 terrorist attacks, the misuse of ionizing radiation or the use of nuclear devices as weapons of terrorism has been recognized as a major public health threat [1-4]. Radiation exposure can cause damage in every major organ system [4,5]. Acute radiation syndrome (ARS) is defined as the signs and symptoms of exposure to radiation. These symptoms develop after a partial or total body exposure to a high dose of radiation. These injuries are more severe in areas where cells have a high turnover rate such as the hematopoetic system, gut and cerebrovascular system. Despite advances in understanding of acute radiation sickness, its management is mainly supportive. The research area of developing radiomitigators, agents that benefit at a post-exposure stage, has been given top priority for radiological nuclear threat countermeasures [6-8]. Although efforts aimed at radiation coutermeasures were initiated more than half a century ago, an urgent unmet medical need still exists for an effective therapy for people suffering from complications of radiation sickness or ARS.
Ghrelin is a 28-amino acid peptide principally produced in endocrine cells of the stomach, termed X/A-like or ghrelin cells, and particularly found in the gastric fundus [9-11]. The biological effects of ghrelin are mediated through the growth hormone secretagoue receptor type 1a (GHSR1a, ghrelin receptor), a 7 transmembrane domain Gq protein-coupled receptor. Ghrelin is the only identified endogenous ligand for this receptor. Ghrelin was reported to induce growth hormone release through the pituitary GHSR1a stimulation [12-14]. However, a large body of evidence has indicated other physiological functions of ghrelin which are mediated by central and peripheral ghrelin receptors [15]. Ghrelin has been linked to the regulation of pituitary hormone secretion, feeding, energy homeostasis, gastrointestinal function, cardiovascular system and immune system. The wide distribution of ghrelin receptors suggests multiple paracrine, autocrine and endocrine roles of ghrelin [16-18]. Exogenous administration of ghrelin in animal models of injuries attenuates systemic inflammation [19-22], lung injury [23], gastrointestinal injury [24] and brain injury [25].
The present application addresses the need for treatment of victims of ARS by using ghrelin as a radiomitigator.